Abstract
The aim of the present study was to determine the effects of ulinastatin (UTI) on brain injury in rats subjected to cardiopulmonary resuscitation (CPR) following asphyxial cardiac arrest (CA) and identify the underlying mechanisms. In total, 100 healthy male Wistar rats were randomly divided into control and treatment groups (n=50). After 4 min of asphyxial CA, all the rats were immediately subjected to CPR. The treatment group animals were administered 15 mg/kg UTI at the onset of resuscitation. The mortality rate in the two groups was recorded at 24 h post-resuscitation. In addition, neurological function was evaluated at 24, 48 and 72 h post-resuscitation using a neurological deficit scale (NDS). Furthermore, the effects of UTI on the Toll-like receptor 4 (TLR4) signaling pathway in brain tissues were determined by assessing TLR4 mRNA expression, nuclear factor (NF)-κB activity and tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels at 1, 3, 6, 12, 24, 48 and 72 h post-resuscitation. After 24 h, the mortality rate significantly decreased in the treatment group when compared with the control animals (10 vs. 30%; P<0.05). Additionally, an overt improvement was observed in the NDS score following UTI treatment when compared with the control (P<0.01). Finally, statistically significant decreases in the levels of TLR4 mRNA expression, NF-κB activity and TNF-α and IL-6 were observed in the treatment group at each time point (P<0.01). Therefore, UTI treatment at the onset of CPR significantly inhibits the TLR4 signaling pathway, thereby alleviating the inflammatory responses following resuscitation and improving neurological function.
Highlights
Statistical data show that ~1 million patients with cardiac arrest (CA) are recorded annually in the United States and Europe [1]
No statistically significant differences were observed in the baseline characteristics, including the body weight, heart rate (HR), mean arterial pressure (MAP) and neurological deficit scale (NDS), between the two groups
The Toll‐like receptor 4 (TLR4) inflammatory signaling pathway has previously been reported to play a critical role in brain injury following cardiopulmonary resuscitation (CPR), since brain injury has been shown to be alleviated by inhibiting the TLR4 signaling pathway via hypoxic preconditioning [7]
Summary
Statistical data show that ~1 million patients with cardiac arrest (CA) are recorded annually in the United States and Europe [1]. Organ injury following successful CPR from CA is considered to be associated with systemic inflammatory responses; levels of various cytokines and lipopolysaccharide (LPS) have been shown to be markedly elevated in patients that have been successfully resuscitated from CA [4,5]. The dynamic changes in the levels of inflammatory cytokines and LPS have been shown to be closely associated with prognosis in patients that have undergone CPR [6]. Under cerebral ischemia and anoxia, the activated TLR4 promotes the expression of nuclear factor (NF)‐κB and induces the production of cytokines, such as tumor necrosis factor (TNF)‐α and interleukin (IL)‐6, thereby causing inflammation and neurological injury [7]. It is hypothesized that the TLR4 signaling pathway may be inhibited by hypoxic preconditioning to attenuate inflammatory responses and neurological injury; protecting brain function.
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